Background: Negative symptoms in schizophrenia remain a challenge with limited therapeutic strategies. The novel compound RG7203 promotes reward learning via dopamine D1-dependent signaling and therefore holds promise, especially to improve the apathy dimension of negative symptoms. When tested as add-on to antipsychotic medication, apathy did not change significantly with RG7203 versus placebo. However, the response varied across patients, and a subset showed clinically relevant improvement of apathy. It remains unclear if these interindividual differences are related to neurobiological correlates.

Methods: Due to the predominant binding of RG7203 in the striatum, we investigated how apathy changes with RG7203 are related to changes in cortico-striatal connectivity by computing rank correlations (r_s ). In a post hoc exploratory analysis, we focused on cortico-striatal circuits that have been associated with apathy and previously showed connectivity alterations in schizophrenia. In a double-blind, 3-way randomized and counterbalanced crossover study, resting-state functional magnetic resonance imaging was acquired from 24 individuals with schizophrenia following a 3-week administration of placebo, 5 mg, or 15 mg of RG7203 as an add-on to antipsychotics.

Results: We found that 5 mg or 15 mg of RG7203 did not lead to significant changes in striatal connectivity. However, changes in the apathy response across individuals were reflected by striatal connectivity changes. Apathy improvement with 5 mg and 15 mg RG7203 vs. placebo was associated with increased striatal connectivity to paracingulate (r_s  = - 0.58, p = 0.047 for both doses) and anterior cingulate regions (r_s  = - 0.56, p = 0.047 for both doses). Such associations were not observed for the negative symptom dimension of expressive deficits. We additionally observed that lower striatal connectivity to paracingulate and anterior cingulate regions during placebo was linked to greater apathy improvement during RG7203 treatment at both doses (r_s  = 0.61-0.79 and p = 0.0002-0.02 across regions and doses).

Conclusions: These findings suggest that striatal connectivity with the paracingulate gyrus and anterior cingulate cortex may be associated with apathy modulation under RG7203 treatment. Replication and further elaboration of these findings in larger clinical studies could help to advance biologically informed and personalized treatment options for negative symptoms.

Trial registration: NCT02824055, registered on ClinicalTrials.gov (2016-06-21).